Our work has contributed significantly to evidence-based guidelines as adjunct therapy for the treatment of PAH patients in an updated treatment algorithm published by the American College of Cardiology (ACC). Findings from our RCT contributed to the ACC suggesting an upgrade to the recommendation for rehabilitation and exercise training for patients with PAH to Class 1 with a Level of Evidence: A. (Galie et al, 2013). While the benefits of aerobic training are proven for patients who have chronic obstructive pulmonary disease and chronic heart failure, its utility for patients with pulmonary hypertension (PH) has been unclear. In our study, we are seeking to understand the cardiorespiratory mechanisms that limit peak oxygen consumption (VO2) in patients with PH and to determine whether these mechanisms are reversible by aerobic exercise training. We also focus on relationships between indices of these mechanisms and indices of performance such as 6-minute walk distance, peak treadmill work rate, and peak exercise time. We are using a battery of self-report scales to investigate the effect of aerobic training on mood, physical activity, fatigue, and exercise readiness. Thus, our clinical trial is aimed at determining, in patients with PH, the gross mechanism by which cardiorespiratory function is limited, whether aerobic exercise training reverses this mechanism, the extent to which reversal of the limiting mechanism actually improves physical performance; and the effect of aerobic training on health related quality of life and physical activity. This project has two main clinical research arms. The first is a phase II clinical trial that evaluates the safety and effectiveness of aerobic exercise training on cardiorespiratory fitness and health related quality of life in patients with PH. After screening and physician exam, patients with PH qualifying for study first complete a 6-minute walk test. After a 45-minute rest period, the subjects then complete self-report questionnaires on general fatigue, mood, physical activity, and overall quality of life. Patients then undergo symptom-limited peak treadmill exercise tests to volitional exhaustion. During the symptom-limited treadmill tests, cardiorespiratory measurements are made including pulmonary gas analyses, cardiac output, and near infrared spectroscopic measures of muscle oxygen extraction. After the test battery is complete the subject is randomized to either a protocol of patient education plus aerobic exercise training or patient education only. Those in the education plus exercise group attend classes on topic of importance regarding living with PH as well as three weekly sessions of treadmill walking exercise at an intensity of 70 to 80 percent of their heart rate reserve. Patients exercise for 30 to 45 minutes per session. The education only group receives identical education classes but does not exercise. Both the education plus exercise training and the education only regimens last for a duration of 10 weeks. Patients in both groups repeat all of the 6-minute walk test, questionnaires, and the treadmill tests. Pre- and post-training changes are compared between the groups. Main outcome variables are peak oxygen consumption and 6-minute walk distance. In the second arm of the project, baseline symptom-limited peak treadmill test results in the patients with PH will be compared to results of sedentary but otherwise healthy control subjects. We will determine if muscle oxygen extraction, and cardiac output is diminished in the patients with PH at baseline. Moreover, this study arm will help us to determine whether, in patients with PH, exercise training-induced changes in the physiological response pattern trend toward normal. There are also two substudies in this project. In the first substudy, subjects in the control group crossover to an exercise only group. The group originally receiving education only will complete the 6-minute walk, questionnaires, and peak treadmill test. Following an exercise training regimen that is identical to the education plus exercise group, the group originally receiving education only will again undergo these tests. Data will be compared before and after training. This substudy will discern the cardiorespiratory adaptations to exercise between the education plus exercise group and the group originally receiving only education. In the second substudy, we are examining the training adaptation in patients with interstitial lung disease (ILD) who do not have PH. Patients with ILD will undergo an exercise training regimen identical to the one used for training patients with PH. Responses and adaptations will be compared. This substudy is important for data interpretation since many of our patients with PH also have ILD. Total Number of Subjects Enrolled = 97 Total Number of Subjects Enrolled in the current year = 8 Total Number of Subjects Enrolled that dropped = 9 Total Number of Subjects Enrolled that dropped this year = 0 Pulmonary Hypertension = 30 Interstitial Lung Disease = 15 Healthy = 52 Though the sample size was small, our RCT has shown that trained PAH patients reached higher levels of physical activity, decreased fatigue severity, improved 6-min walk distance (6MWD), cardiorespiratory function, and patient-reported quality of life as compared with untrained controls. Our research was also referenced in a panel discussion on Exercise and Pulmonary Rehabilitation at the 2014 International PH Association Conference in Indianapolis, IN, where the consensus of medical opinion stated exercise in a supervised setting is critical for PH patients (Bull et al, 2014). Interpreting our findings to date has provided our team with opportunities to identify additional important research questions within our means to answer. We will also utilize healthy volunteer data collected in this study to compare to data collected in our randomized controlled exercise trial for patients with interstitial lung disease without pulmonary hypertension. The basis for the randomized trial for ILD and exercise was established by our work with PAH and exercise where we observed more efficient cardiorespiratory function, increased physical work capacity, and improved health related quality of life (HRQoL), following AET in an uncontrolled arm of patients with ILD without pulmonary hypertension. Publications in the last year: Keyser, R.E., Christensen, E.J., Woolstenhulme, J., Drinkard, B., Quinn, A., Connors, G., Weir, N.A., Nathan, S. D., Chan, L.E. Changes in fatigability following intense aerobic exercise training in patients with interstitial lung disease. Respiratory Medicine 2015 April 109(4):517-25. doi: 10.1016/j.med.2015.01.021. Keyser, R.E., Woolstenhulme, J., Chin, LMK, Nathan, S.B., Weir, N.A., Connors, G., Drinkard, B., Lamberti, J., and Chan, L.E. Cardiorespiratory function before and after aerobic exercise training in patients with interstitial lung disease. Journal of Cardiopulmonary Rehabilitation and Prevention 2015 January/February 35(1):47-55. doi:10.1097/HCR.0000000000000083.